Many chronic pain conditions remain difficult to treat, presenting a high burden to society. Conditions such as complex regional pain syndrome may be maintained or exacerbated by sympathetic activity. The discovery of abnormal connections between sympathetic and sensory neurons, e.g. the sprouting of sympathetic fibers into the sensory ganglia (DRG) after peripheral nerve injury, offered a possible explanation, but studies of this effect yielded conflicting findings. New tools and knowledge are now available to overcome some limitations of previous work in this field, as proposed: 1) The contribution of sympathetic transmitters other than norepinephrine (NE) will be examined. Many previous studies relied solely on NE antagonists, ignoring known sympathetic co-transmitters such as ATP, which is particularly important in pathological conditions. New reagents for specific ATP receptor subtypes will help investigate its role. 2) Functional studies of the sympathetic-sensory neuron connection were very limited. The proposed research will use a described new preparation for stimulating the sympathetic fibers that have sprouted into the DRG while recording intracellularly many parameters of sensory neuron excitability. 3) The possible interaction of satellite glial cells and sympathetic sprouts has not been investigated. The importance of activated glia in pathological pain has been recognized only recently. Experiments will test possible mechanisms by which reverberating interactions between sprouting sympathetic fibers, sensory neurons, and satellite glia cells might play key roles in initiating the pathological pain state. 4) Sympathetic effects on sensory neurons may shift from early excitatory to later inhibitory ones, accounting for conflicting findings. This shift occurs in other model systems of chronic inflammation. The function of sympathetic sprouts at later time points will be examined. 5) The role of local inflammation in promoting sympathetic sprouting has not been fully recognized. Local DRG inflammation is sufficient to induce sprouting, and can enhance sprouting caused by axotomy. Functional mechanisms and behavioral relevance of sympathetic - sensory neuron interactions in pain models will be examined using 3 specific aims: SA1: To characterize functional effects of sympathetic fibers on DRG excitability, spontaneous activity and pain behavior, including determining the effects of a very limited form of surgical sympathectomy that eliminates sprouting in a single DRG. SA2: To determine whether sympathetic transmitters in addition to NE play important excitatory roles in abnormal sympathetic-sensory neuron interactions, focusing on possible roles of ATP and satellite glia cells. SA3: To determine the interactions between localized inflammation, sympathetic outgrowth and neuropathic pain. We will determine whether sympathetic spouts regulate inflammatory responses in the early phases of two pain models, as suggested by work in other models of chronic inflammation. The proposed experiments will reinvigorate the study of sympathetic-sensory interactions in chronic pain conditions, and help find new approaches to this serious clinical problem. PUBLIC HEALTH RELEVANCE: Chronic pain conditions such as CRPS are common, long-lasting, and debilitating. We propose to continue the study of sympathetic component in neuropathic pain. Using a rat/mouse model, we will determine how abnormal activity, inflammation, ATP release affect sympathetic outgrowth and the neurons that sense pain.